Fibroblast growth factor 21 (FGF21) is a member of the FGF family which produces beneficial effects on lipid levels, body weight and glucose metabolism in animals. For example, overexpression of FGF21 in transgenic mice has been shown to result in reduced glucose and triglyceride levels, and resistance to diet-induced obesity. (Kharitonenkov et al. (2005), J. Clin. Invest. 115; 1627-1635). Moreover, the administration of exogenous FGF21 to rodents and primates results in normalization of blood glucose levels, reduced triglyceride and cholesterol levels, improved glucose tolerance and improved insulin sensitivity. (Kharitonenkov et al. (2007), Endocrinol. 148:774-781) FGF21 administration in experimental animal models has been shown to reduce body weight and body fat by increasing energy expenditure, physical activity, and metabolic rate. (Long and Kharitonenkov (2011) Biochim. Biophys. Acta 1812:791-795).
FGF21 signaling is mediated through its interaction with a receptor complex that includes βKlotho (KLB) and one of three different FGF receptors (FGFR1c, FGFR2c or FGFR3c). (Ogawa et al. (2007), Proc. Natl. Acad. Sci. USA 104:7432-7437; Suzuki et al. (2008), Mol. Endocrinol. 22:1006-1014). It is believed that the main functional receptor for FGF21 signaling in vivo is the KLB/FGFR1c complex (this complex is referred to herein as “FGF21R”).
Pharmacological activation of FGF21 signaling has been proposed for the treatment of various diseases and disorders in humans including type-2 diabetes, obesity, dyslipidemia, and other metabolic conditions. Proposed therapeutic strategies for activating FGF21 signaling include administration of recombinant FGF21, and the use of agonistic antibodies that bind FGFR1 or the KLB/FGFR1c complex (US2011/0135657; US2012/0294861; US2013/0330336; WO 2011/130417; WO2012/170438; WO2013/033452). Nonetheless, there exists a need in the art for novel avidity-driven therapeutic approaches that take advantage of FGF21's beneficial metabolic properties.